Matched-samples comparison of intramuscular versus vaginal progesterone for luteal phase support after in vitro fertilization and embryo transfer

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1 Matched-samples comparison of intramuscular versus vaginal progesterone for luteal phase support after in vitro fertilization and embryo transfer Naveed Khan, M.D., a Kevin S. Richter, Ph.D., a Tasha L. Newsome, a Emily J. Blake, M.D., b and Vladimir I. Yankov, M.D. b a Shady Grove Fertility Reproductive Science Center, Rockville, Maryland; and b Ferring Pharmaceuticals, Inc., Parsippany, New Jersey Objective: To evaluate vaginal compared to intramuscular (IM) progesterone supplementation for luteal phase support after in vitro fertilization and embryo transfer (IVF-ET). Design: Retrospective matched-samples comparative study. Setting: Private infertility center. Patients(s): Two hundred forty patients undergoing IVF-ET. Intervention(s): Patients received either vaginal progesterone supplementation in the form of Endometrin 100 mg twice a day (n ¼ 12), Endometrin 100 mg three times a day (n ¼ 11), or Crinone 8% gel 90 mg every day (n ¼ 17), or 50 mg every day IM progesterone in oil (n ¼ 200). Main Outcome Measure(s): Clinical intrauterine pregnancy rates, pregnancy loss, and live birth rates. Result(s): Among patients using vaginal progesterone, there were no statistically significant differences in patient characteristics and clinical outcomes, regardless of the type of vaginal progesterone used. There were no differences in outcomes between the vaginal and IM progesterone treatment groups. There were 20 pregnancies (50.0%) among patients treated with vaginal progesterone and 103 pregnancies (51.5%) among matched IM progesterone patients. The live birth rates were 47% in the IM versus 47.5% in the vaginal progesterone groups. There were no statistically significant differences in miscarriage rates between groups. Conclusion(s): There are no significant differences in treatment outcomes between vaginal and IM progesterone supplementation, yielding similar clinical pregnancy, miscarriage, and live birth rates. (Fertil Steril Ò 2009;91: Ó2009 by American Society for Reproductive Medicine.) Key Words: Vaginal, intramuscular, progesterone, luteal phase support, in vitro fertilization, pregnancy rate, live birth rate Progesterone production is a key component of the luteal phase that is necessary for successful implantation of a developing embryo. The ovarian follicle, which primarily secretes estrogen before ovulation, forms the corpus luteum and secretes progesterone after ovulation. The progesterone induces a secretory transformation of the uterine glands, increases vascularity of the endometrial lining, and stabilizes the endometrium in preparation for embryo implantation. If pregnancy does not occur after about 12 days, the corpus luteum progesterone production wanes and menstruation ensues. However, under the influence of human chorionic gonadotropin (hcg), the corpus luteum will continue to produce progesterone and maintain the Received February 11, 2008; revised and accepted March 24, 2008; published online June 13, N.K. has nothing to disclose. K.S.R. has nothing to disclose. T.L.N. has nothing to disclose. Presented at the 55th Annual Scientific Meeting of the Pacific Coast Reproductive Society, Rancho Mirage, California, April 18 22, Conflict of Interest: the randomized study of different forms of vaginal progesterone supplementation was sponsored by Ferring Pharmaceuticals, Inc. Drs. Blake and Yankov are employees of Ferring Pharmaceuticals, Inc. Reprint requests: Kevin S. Richter, Ph.D., Shady Grove Fertility Reproductive Science Center, Shady Grove Road, Suite 400, Rockville, Maryland (FAX: ; kevin.richter@integramed. com). pregnancy until the hormonal shift to placental progesterone production toward the end of the first trimester (1). Some components of assisted reproduction, such as the use of gonadotropin-releasing hormone agonists (GnRHa) or antagonists, can effect the production of progesterone. Gonadotropin-releasing hormone agonists and antagonists are used in in vitro fertilization (IVF) protocols to prevent the luteinizing hormone (LH) surge and inhibit ovulation. However, they can also induce an iatrogenic luteal phase defect (2) because the LH suppression can persist up to 10 days after discontinuation of these medications (3). Continuous LH stimulation on the corpus luteum is important for adequate progesterone production (4). Furthermore, the IVF egg retrieval process results in aspiration of granulosa cells along with the mature oocytes, and can interfere with the natural production of progesterone and estrogen, thus also resulting in the disruption of a normal luteal phase (5, 6). To help correct for this hormonal inadequacy in IVF cycles, various luteal phase supplementation therapies have been developed with either single or combined agents, such as estrogen, progesterone, or hcg. The specific administration protocols still remain an area of controversy. Two recent meta-analyses of randomized controlled trials (RCTs) found /09/$36.00 Fertility and Sterility â Vol. 91, No. 6, June doi: /j.fertnstert Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 that luteal phase support after assisted reproduction with either intramuscular (IM) hcg or progesterone resulted in higher pregnancy rates compared with placebo or no treatment (7, 8). One of these meta-analyses suggested that pregnancy rates were higher with hcg than progesterone (8), whereas the other, and much larger, meta-analysis found that hcg or progesterone supplementation provided equivalent results (7). The use of hcg also doubled the risk of ovarian hyperstimulation syndrome (OHSS) compared with the use of progesterone (7). Other RCTs have shown that the addition of estrogen to progesterone in the luteal phase following a long GnRHa protocol further improves implantation rates (9, 10). Poor corpus luteum function, whether because of inadequate intrinsic functioning or because of exogenous medications such as GnRHa or antagonists, produces a luteal phase defect that can result in pregnancy loss (2). As a result of improved pregnancy rates and lower OHSS risk relative to hcg, supplemental progesterone is most commonly used for luteal phase support following IVF and embryo transfer (IVF-ET). Progesterone support may be either supplementation to progesterone produced by the corpus luteum or may provide complete support of the early pregnancy (as in frozen embryo transfer cycles). Luteal phase progesterone supplementation has been shown to significantly increase pregnancy rates (7, 8). However, the relative efficacy of alternative routes of administration is less clear. Current formulations of progesterone can be delivered via many different routes including oral, injection, and vaginal routes. Intramuscular progesterone in oil is regarded as the gold standard of progesterone supplementation, and has been in use longest by fertility centers, despite not being U.S. Food and Drug Administration (FDA) approved for this indication or for use in pregnancy. Intramuscular progesterone is rapidly absorbed, and produces measurable plasma concentration levels in 2 to 8 hours, which remain elevated for up to 72 hours. However, the injections can be painful, cause sterile abscesses or bleeding, are inconvenient, and can induce significant patient anxiety. In addition, some women can develop an allergy to the oil used to suspend the progesterone. Oral progesterone (Prometrium) has been used for luteal phase supplementation, especially in intrauterine insemination cycles. Although the oral route is very convenient, there are several significant disadvantages. The rapid metabolization that occurs because of the first-pass effect in the liver renders most of the drug ineffective (11). Progesterone metabolites can cause significant side effects such as fatigue, dizziness, and drowsiness. Oral progesterone is more effective at raising serum progesterone levels (12) than at raising progesterone levels within the uterine lining itself where the effect is needed most. Although inconclusive because of low sample sizes, meta-analyses show that oral may be the least efficacious route of progesterone administration, with suggestive trends toward better outcomes with either IM or vaginal administration (7). There are several formulations of vaginal progesterone including gels (Crinone, Prochieve), suppositories, and a new micronized progesterone vaginal insert (Endometrin). The advantage of vaginal administration of progesterone is that it specifically targets the hormonal effects to the uterus and pelvis, and minimizes the adverse systemic sedating side effects. Compared with IM administration, vaginal administration results in significantly lower serum progesterone concentrations, but much higher concentrations of progesterone in endometrial tissues (13, 14) because of first uterine pass effect. Compared with oral progesterone administration, vaginal administration results in greater bioavailability with less variability (15). Drowsiness is approximately twice as frequent with oral rather than vaginal progesterone administration (16). The various vaginal formulations have specific therapeutic issues. The gel formulations accumulate a significant vaginal buildup that can be uncomfortable for patients and induces vaginal irritation. Vaginal suppositories are not commercially available, and are compounded by individual pharmacists, resulting in inconsistent and variable delivery of progesterone and making them less amenable for study in a national RCT. Furthermore, the suppositories can be messy as they liquefy at body temperature, which leads to leakage, residue, irritation, and yeast infections (17). TheFDArecentlyapprovedanewprogesterone supplement for use in assisted reproductive technology (ART) cycles and for use in pregnancy. Endometrin is a vaginal tablet composed of micronized progesterone that is administered into the vaginal vault with an applicator. Endometrin administration results in a rapid rise in serum progesterone concentration, and higher peak serum concentrations within a shorter time than does administration of a vaginal gel formulation, reaching steady-state values within 24 to 36 hours after the initiation of treatment rather than 5 or more days (18). Before FDA approval of Endometrin, the only FDAapproved medication for progesterone support following IVF-ET was the vaginal gel Crinone. Therefore, Crinone was used as the control in this preapproval RCT of Endometrin. However, in practice, the gold standard, and the standard protocol used at our center for luteal phase progesterone support, was IM progesterone. The relative efficacy of vaginal versus IM progesterone administration is therefore an important question for us and many other clinicians. The objective of this study was to evaluate the effectiveness of vaginal progesterone supplementation compared with IM progesterone supplementation for luteal phase support after IVF-ET. We compared the vaginal preparations of micronized progesterone (Endometrin) and Crinone gel 8% to IM progesterone in oil to determine if there were any differences in pregnancy rates, delivery rates, or miscarriage. MATERIALS AND METHODS All patients included in this comparison underwent IVF-ET at Shady Grove Fertility during August through December In the cycle preceding IVF treatment, patients were given monophasic oral contraceptives for 21 days starting between days 1 to 3 of the menstrual cycle. Suppression of premature ovulation in the treatment cycle was accomplished through use of a long luteal protocol of daily subcutaneous GnRH agonist administration (20 units/day), which was 2446 Khan et al. Vaginal versus IM progesterone for IVF Vol. 91, No. 6, June 2009

3 TABLE 1 Patient and cycle characteristics and clinical outcomes of IVF-ET treatment cycles compared among three forms of vaginal progesterone supplementation for luteal phase support. Endometrin twice a day Endometrin three times a day Crinone every day P value Number of cycles Patient age (years) a Baseline FSH (IU/L) a Endometrium (mm) a Embryos per ET a Clinical PR per cycle 50.0% 45.4% 52.9% 0.93 b Pregnancy loss 1 (at weeks) b Note: ET ¼ embryo transfer. a P values for analysis of variance of three-way comparison. b P values for c 2 comparison. Khan. Vaginal versus IM progesterone for IVF. Fertil Steril started 3 days before completion of the oral contraceptives. Patients were evaluated on menstrual cycle day 2 with ultrasound, to screen for any cyst formation, and estradiol was checked to ensure adequate suppression (estradiol <60 pg/ ml). Gonadotropin releasing hormone agonist dose was reduced to 5 units/day when ovarian stimulation was initiated and continued until the trigger injection. Ovarian stimulation, beginning on cycle day 3, was by a combination of purified or recombinant follicle-stimulating hormone (FSH) and purified human menopausal gonadotropin. Ovulation was triggered by administration of 10,000 IU hcg when two or more follicles had reached a diameter of 18 mm or greater. Oocytes were retrieved 36 hours later, and inseminated either conventionally or by intracytoplasmic sperm injection as appropriate. A maximum of three cleavage stage or two blastocyst stage embryos were transferred on either postretrieval day 3, or days 5 or 6, respectively, depending on the quality and quantity of embryos available. In addition to progesterone for luteal support, all patients received concomitant estrogen supplementation during the luteal phase with Estrace 2 mg by mouth twice a day starting the evening of retrieval. Patients receiving vaginal progesterone supplementation for luteal support were consenting participants in an institutional review board-approved phase III multicenter RCT investigating a novel formulation of progesterone (Endometrin, Ferring Pharmaceuticals, Inc., Parsippany, NJ) sponsored by Ferring Pharmaceuticals, Inc. (19). Inclusion criteria for this clinical trial were maximum age of 42 years, maximum day 3 FSH of 15 IU/L, maximum day 3 E 2 of 80 pg/ml, maximum body mass index of 34, a normal uterine cavity, and a minimum of three oocytes retrieved. Donor oocytes, preimplant genetic diagnosis, and abnormal LH (>13.4 IU/L), PRL (>23.2 ng/ml), or TSH (>3.59 uiu/ml) were excluded. As part of this clinical trial, 40 IVF patients at Shady Grove Fertility were randomized to one of three forms of vaginal progesterone supplementation for luteal phase support after IVF-ET. Endometrin 100 mg was received twice a day by 12 patients, and three times a day by 11 patients, and Crinone 8% gel 90 mg (Serono Laboratories, Inc., Norwell, MA) was received every day by 17 patients. Treatment was initiated on the day following oocyte retrieval and continued for 10 weeks (or until negative pregnancy test). The patients receiving vaginal progesterone supplementation for luteal support were retrospectively matched to other patients undergoing IVF-ET at Shady Grove Fertility during the same time period, and receiving our standard protocol of IM progesterone in oil for luteal phase support (50 mg every day beginning on the night of oocyte retrieval, continued for 10 weeks or until negative pregnancy test). Patients were matched for age, baseline FSH, endometrial thickness on the day of hcg trigger administration, stage of embryo transfer (cleavage or blastocyst), and number of embryos transferred. Our patient population was sufficiently large to identify five unique well-matched patients receiving IM progesterone for each patient receiving vaginal progesterone, for a total sample size of 200 IM progesterone patients. To evaluate the comparability of the two treatment groups, patient age, baseline FSH, endometrial thickness on the day of hcg trigger, and numbers of embryos per transfer were compared by t test. Rates of clinical intrauterine pregnancy (defined by ultrasound identification of a gestational sac) and live birth were compared between vaginal and IM progesterone by c 2 analysis. Because of its low frequency of occurrence, pregnancy loss was compared between IM and vaginal progesterone groups by Fisher s exact test. Analyses were conducted using JMP statistical software (SAS Institute Inc., Cary, NC). A P value of %.05 was considered statistically significant. RESULTS Among patients using vaginal progesterone for luteal phase support, patient characteristics and clinical outcomes were Fertility and Sterility â 2447

4 TABLE 2 Patient and cycle characteristics and clinical outcomes of IVF-ET treatment cycles compared between vaginal and intramuscular progesterone supplementation for luteal phase support. Vaginal progesterone IM progesterone P value Number of cycles Patient age (years) a Baseline FSH (IU/L) a Endometrium (mm) a ET stage (% blast) b Embryos per ET a Clinical PR per ET (%) 20 (50.0%) 103 (51.5%) 0.86 b First trimester losses 0 6 (5.8%) 0.59 c Second trimester losses 1 (5.0%) 3 (2.9%) 0.51 c Total preg losses 1 (5.0%) 9 (8.7%) 1.00 c Live birth per ET (%) 19 (47.5%) 94 (47.0%) 0.95 b Note: ET ¼ embryo transfer. a P values for t test. b P values for c 2 comparison. c P values for Fisher s exact test. Khan. Vaginal versus IM progesterone for IVF. Fertil Steril similar, with no statistically significant differences, regardless of the type of vaginal progesterone supplementation used (Table 1). The different types of vaginal progesterone supplementation were therefore pooled for comparison to patients receiving IM progesterone supplementation. The matching of patients receiving vaginal progesterone supplementation to control patients receiving the standard IM progesterone was very effective. The developmental stage of embryos at transfer matched perfectly. Patient age, baseline FSH, endometrial thickness on the day of hcg administration, and the number of embryos per transfer were all very similar between the two treatment groups (Table 2), with no differences approaching statistical significance. Treatment outcomes were also very similar between the IM and vaginal progesterone treatment groups (Table 2). The live birth rate was high and nearly identical between treatment groups, with a 47.0% birth rate in the IM progesterone group versus a 47.5% birth rate in the vaginal progesterone group. There were 20 pregnancies (50.0%) among patients treated with vaginal progesterone, and 103 pregnancies (51.5%) among matched patients treated with IM progesterone. Among the patients treated with vaginal progesterone, there were no first trimester miscarriages and one second trimester miscarriage, whereas among the patients treated with IM progesterone there were six first trimester losses and three second trimester losses. There were no statistically significant differences in any treatment outcomes between groups. DISCUSSION Progesterone has been shown to be readily absorbed vaginally. Miles et al. (13) compared endometrial tissue levels of progesterone administered vaginally compared with IM administration. In this study, 20 estrogen-primed agonadal women were randomized to receive either 200 mg vaginal micronized progesterone capsules or progesterone 50 mg IM. After 7 days of progesterone, endometrial sampling was performed and the specimen results demonstrated that women taking vaginal progesterone had an eightfold higher endometrial progesterone concentration than the women taking progesterone via the IM route. In a study by Gibbons et al. (20) 54 women underwent endometrial biopsy after receiving intravaginal Crinone 8% twice daily. All the women developed appropriate in-phase late luteal phase endometrial linings. In addition, women using donor oocytes were randomized into receiving either vaginal Crinone 8% or progesterone 100 mg IM, and both groups had similar ongoing pregnancy rates. A new micronized progesterone (Endometrin) was approved by the FDA for luteal phase support in women undergoing ART treatment cycles and for use in early pregnancy in Endometrin is a tablet that is administered intravaginally via applicator. Comparison of the results between Endometrin and Crinone within our center were very similar to results of the entire multicenter RCT that included >400 patients per treatment group (19), with nearly identical pregnancy and birth rates for either formulation, justifying the pooling of these two formulations of vaginal progesterone supplement for comparison to IM progesterone. Our study suggests that rates of pregnancy, miscarriage, and live birth are equivalent between patients treated with vaginal progesterone and those treated with IM progesterone for luteal phase support after IVF-ET. There was no indication of lower pregnancy or live birth rates from vaginal rather than IM progesterone Khan et al. Vaginal versus IM progesterone for IVF Vol. 91, No. 6, June 2009

5 Although ours was not a prospective randomized study, an effort was made to make the two treatment groups highly comparable with respect to many potentially confounding variables known to influence IVF-ET treatment outcomes. The stage of embryo transfer was identical in the vaginal and IM groups (35% blastocyst transfer) and patient age, baseline FSH, endometrial thickness, and the number of embryos per transfer were nearly identical between the vaginal and IM progesterone treatment groups. However, the power of our comparison is relatively limited because of the low sample size (n ¼ 40) of patients receiving vaginal progesterone. Our results are in general agreement with other previous comparisons of vaginal to IM progesterone. The most recent meta-analysis of RCTs found no difference in clinical pregnancy rates and miscarriage rates in >1,700 patients from 10 RCTs (7). However, a statistically significant difference in live births per transfer was seen in favor of IM progesterone. This apparent contradiction in the live birth results was based on only two of the RCTs with a total of 500 subjects, and the estimated effect size (with near doubling in birth rate for IM versus vaginal progesterone, 42% vs. 23%) does not seem credible. Many of the previous studies comparing intravaginal progesterone to IM progesterone were not prospective, randomized, or large enough to have enough statistical power to make any definitive conclusions (21, 22). Yanushpolsky et al. (23) published an interim report on 215 women enrolled in a prospective randomized controlled study comparing intravaginal to IM progesterone administration. One hundred fivewomen were given Crinone 8% vaginal gel and were compared with 110 women receiving IM progesterone. Pregnancy rates, implantation rates, ongoing pregnancy rates, and first trimester spontaneous abortion rates were similar in the two groups. The patients using vaginal progesterone experienced fewer side effects overall and reported significantly higher satisfaction scores. An earlier study in 2001 by the same group found lower implantation and clinical pregnancy rates with Crinone compared with IM progesterone (24). However, these results may have been significantly affected by the lack of stratification for female age and ovarian reserve, resulting in a skewed proportion of women over the age of 40 in the Crinone group. The next step is to proceed with a fully randomized prospective trial comparing vaginal Endometrin to IM progesterone. From the results of our current study and other published data, we can feel reassured that any differences between the two therapies would be small. A sample size of 350 patients randomized between the two groups would provide an approximate power of 80% to detect a difference of 15% in delivery rates (as had been shown in some studies comparing vaginal Crinone to IM progesterone). Our study is the first study comparing Endometrin to Crinone to IM progesterone since its FDA approval earlier this year. Larger scale randomized studies are needed to confirm the clinical equivalence of vaginal and IM delivery of progesterone. In the absence of clear evidence demonstrating a clinically significant difference in efficacy, the choice of the route of progesterone administration may be based on other criteria such as cost or tolerability. REFERENCES 1. Daya S. Ovulation induction for corpus luteum deficiency. Semin Reprod Endocrinol 1990;8: DiLuigi AJ, Nulsen JC. Effects of gonadotropin-releasing hormone agonists and antagonists on luteal function. Curr Opin Obstet Gynecol 2007;19: Smitz J, Devroey P, Camus M, Deschacht J, Khan I, Staessen C, et al. The luteal phase and early pregnancy after combined GnRH-agonist/HMG treatment for superovulation in IVF or GIFT. Hum Reprod 1988;3: Vande Wiele RL, Bogumil J, Dyrenfurth I, Ferin M, Jewelewicz R, Warren M, et al. 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6 20. Gibbons WE, Toner JP, Hamacher P, Kolm P. Experience with a novel vaginal progesterone preparation in a donor oocyte program. Fertil Steril 1998;69: Chantilis SJ, Zeitoun KM, Patel SI, Johns DA, Madziar VA, McIntire DD. Use of Crinone vaginal progesterone gel for luteal support in in vitro fertilization cycles. Fertil Steril 1999;72: Schoolcraft WB, Hesla JS, Gee MJ. Experience with progesterone gel for luteal support in a highly successful IVF programme. Hum Reprod 2000;15: Yanushpolsky E, Hurwitz S, Greenberg L, Racowsky C, Hornstein MD. Comparison of Crinone 8% intravaginal gel and intramuscular progesterone supplementation for in vitro fertilization/embryo transfer in women under age 40: interim analysis of a prospective randomized trial. Fertil Steril 2007;89: Propst AM, Hill JA, Ginsburg ES, Hurwitz S, Politch J, Yanushpolsky EH. A randomized study comparing Crinone 8% and intramuscular progesterone supplementation in invitro fertilization-embryo transfer cycles. Fertil Steril 2001;76: Khan et al. Vaginal versus IM progesterone for IVF Vol. 91, No. 6, June 2009